Design, synthesis and bioevaluation of 2-mercapto-6-phenylpyrimidine-4-carboxylic acid derivatives as potent xanthine oxidase inhibitors

Ailong Shi; Lichao Zhang; He Wang; Sibo Wang; Mingzheng Yang; Qi Guan; Kai Bao; Weige Zhang

doi:10.1016/j.ejmech.2018.06.009

Design, synthesis and bioevaluation of 2-mercapto-6-phenylpyrimidine-4-carboxylic acid derivatives as potent xanthine oxidase inhibitors

Eur J Med Chem. 2018 Jul 15:155:590-595. doi: 10.1016/j.ejmech.2018.06.009. Epub 2018 Jun 5.

Authors

Ailong Shi¹, Lichao Zhang², He Wang¹, Sibo Wang¹, Mingzheng Yang³, Qi Guan⁴, Kai Bao⁵, Weige Zhang⁶

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zhangweige2000@sina.com.
³ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁴ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: guanqi@syphu.edu.cn.
⁵ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: baokai@syphu.edu.cn.
⁶ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zhangweige@syphu.edu.cn.

PMID: 29920453
DOI: 10.1016/j.ejmech.2018.06.009

Abstract

A series of 2-mercapto-6-phenylpyrimidine-4-carboxylic acid derivatives (7a‒c, 8a‒e, 9a‒e and 10a‒e) as novel xanthine oxidase inhibitors were designed based on molecular docking, and synthesized by a new method using ketoenol acids and thiourea as the starting materials. In vitro activity assay indicated that most of the designed compounds displayed submicromolar inhibitory potency. Specifically, compound 9b had the most potent enzyme inhibitory activity with the IC₅₀ at 0.132 μM. Steady-state enzyme kinetics indicated that 9b behaved as a mixed-type inhibitor for XO.

Keywords: 2-Mercapto-6-phenylpyrimidine-4-carboxylic acids; Molecular modeling; Structure-activity relationship; Synthesis; Xanthine oxidase inhibitors.

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*
Xanthine Oxidase / antagonists & inhibitors*
Xanthine Oxidase / metabolism

Substances

Enzyme Inhibitors
Pyrimidines
Sulfhydryl Compounds
Xanthine Oxidase